Pain resulting from cancer, particularly cancer that metastasizes to bone, is often extremely painful and profoundly contributes to the erosion of the patients,Ao quality of life. Although cancer pain is often managed effectively with narcotics, the many undesirable side effects associated with these medications limit their use. The development of new and effective treatments for cancer pain is hampered by a paucity of knowledge about the basic neurobiological mechanisms underlying cancer pain. We have been involved in the development of a murine model of cancer pain that allows rigorous exploration of underlying mechanisms and testing of specific hypotheses. The model is based on implantation of osteolytic fibrosarcoma cells in and around the calcaneous bone. This produces spontaneous pain and hyperalgesia, sensitization of C nociceptors in skin overlying the tumor, and degeneration of primary afferent fibers. It was found that TNFa and ET-1 are present in high concentrations at the tumor site and contribute to the hyperalgesia and sensitization. In the proposed studies, a multidisciplinary approach consisting of correlative behavioral, and in vivo and in vitro electrophysiological studies will be used to further investigate tumor-nerve interactions that produce pain. Specifically, we will investigate the role of the capsaicin receptor, TRPV1, and ATP receptors in tumor- evoked hyperalgesia and nociceptor sensitization. In behavioral studies, the effects of receptor selective antagonists delivered to the tumor site upon hyperalgesia will be determined. Similarly, recordings will be made from primary afferent fibers in vivo and antagonists will be used to determine whether these receptor systems contribute to tumor-evoked sensitization of nociceptors. Finally, patch clamp recordings will be made from DRG neurons that are cultured alone or with cancer cells to identify direct effects of the cancer cells on neuronal excitability and signaling via TRPV1 and ATP receptors. These studies will provide new information on functional interactions between tumors and peripheral nerve. Results may have a direct impact on the future development of novel medications for cancer pain that act peripherally at the tumor/nerve level.